Colorectal cancer is the second most common cause of cancer death in the United States. High fat diets are an important risk factor for colon cancer;conversely, estrogens protect against colon carcinogenesis. The mechanisms underlying the detrimental actions of fatty diets and the beneficial effects of estrogens are unclear. However, one compelling hypothesis is that fatty diets contribute to carcinogenesis by increasing colonic concentrations of bile acids, which stimulate cell proliferation and act as tumor promoters. There is strong epidemiological and animal model data linking elevated bile acid concentrations to colorectal cancer. We propose a unifying hypothesis in which the pro-carcinogenic effects of bile acids and the anti- carcinogenic actions of estrogens are mediated through the bile acid receptor FXR and the estrogen receptor beta (ERbeta), respectively. Both receptors are members of the steroid/thyroid hormone receptor family of ligand-activated transcription factors and are abundantly expressed in colon. In the proposed model, activation of FXR induces expression of another nuclear receptor, termed SHP, which suppresses the anti- proliferative actions of ERbeta. In preliminary data, it is shown that activation of FXR causes hyperproliferation of the colonic mucosa and that this effect requires SHP. Notably, induction of SHP correlates with repression of ERbeta both in vitro and in vivo. In this proposal, the roles of FXR, SHP, and ERbeta in colon carcinogenesis will be studied. In Specific Aim 1, the roles of FXR and SHP in proliferation and colon carcinogenesis promoted by bile acids will be examined. In Specific Aim 2, the molecular mechanisms underlying the protective actions of estrogens in colon will be studied. In Specific Aim 3, the mechanism whereby bile acids repress ERbeta expression will be examined. These studies will provide important insights into the complex relationship between bile acids, estrogens, and colorectal carcinogenesis. Moreover, since both FXR and ERbeta can be regulated by small molecule ligands, these studies may reveal novel opportunities for treating and preventing colon cancer.